Abstract
Inherited pathogenic mutations in the mismatch repair (MMR) genes, MSH2, MLH1, MSH6, and PMS2 predispose to Lynch syndrome (LS). However, the finding of a variant or variants of uncertain significance (VUS) in affected
family members complicates the risk assessment. Here, we describe a putative LS family carrying VUS in both MSH2 (c.2768T>A, p.Val923Glu) and MSH6
(c.3563G>A, p.Ser1188Asn). Two colorectal cancer (CRC) patients were
studied for mutations and identified as carriers of
both variants. In spite of a relatively high mean age of
cancer onset (59.5 years) in the family, many CRC patients and the
tumor pathological data suggested that the missense
variation in MSH2, the more common susceptibility gene in LS, would be the predisposing alteration. However, MSH2 VUS was surprisingly found to be MMR proficient in an in vitro MMR assay and a tolerant alteration in silico. By supplying evidence that instead of MSH2 p.Val923Glu the MSH6 p.Ser1188Asn variant is completely MMR-deficient, the present
study confirms the previous findings, and suggests that MSH6
(c.3563G>A, p.Ser1188Asn) is the pathogenic mutation in the family.
Moreover, our results strongly support the strategy to
functionally assess all identified VUS before predictive
gene testing and genetic counseling are offered to a family.
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